Scientists unlock clues to HIV vaccine

Key authors of two studies on HIV structure (from left to right) Bridget Carragher, Jean-Philippe Julien, Ian Wilson, Dmitry Lyumkis and Andrew Ward, all of The Scripps Research Institute. Photo courtesy of the Scripps Research Institute

Key authors of two studies on HIV structure (from left to right) Bridget Carragher, Jean-Philippe Julien, Ian Wilson, Dmitry Lyumkis and Andrew Ward, all of The Scripps Research Institute. Photo courtesy of the Scripps Research Institute

Scientists from La Jolla and New York announced Thursday that they have decoded the structure of a key weapon for the AIDS virus, unlocking a long-sought clue needed to develop an HIV vaccine.

The findings, by teams from The Scripps Research Institute and Weill Cornell Medical College, were published in Science Express, the early online edition of the journal Science.

The two groups used separate methods to peer at the molecular apparatus that allows the AIDS virus to enter host cells and arrived at parallel results around the same time, scientists said.

“I think this has the potential to have huge implications,” said Rowena Johnston, vice president and research director for amfAR, the international HIV/AIDS research foundation based in New York City. She added that the twin studies represent a milestone because they finally identified the structure of the AIDS virus in “the form in which it causes infection.”

That form is the HIV trimer, a molecular assemblage on the surface of the virus that allows it to invade host cells. A 2009 article in the journal Nature titled “Structures of Desire” listed the trimer — also known as a virus spike — as one of the most coveted targets in the field of virology.

Through studies funded by the National Institutes of Health, the Scripps institute and Weill Cornell scientists used two types of advanced instruments to generate matching images of the trimer. But each method ended up mapping different vulnerabilities of the virus.

About 34 million people in the world are living with HIV, the human immunodeficiency virus, and roughly 50,000 new HIV infections are reported each year in the United States, according to the National Institute of Allergy and Infectious Diseases.

Thirty years ago, researchers identified the virus as the cause of acquired immune deficiency syndrome, or AIDS. Since then, antiretroviral drugs have helped slow the progression of HIV in infected patients and reduced its transmission between high-risk people, such as infected mothers and their babies.

Yet the holy grail of AIDS prevention — a vaccine that blocks infection in the first place — has remained elusive.

A big obstacle is the adaptability of HIV, which uses chemical disguises to shield itself from antibodies and continually morphs into new and sometimes drug-resistant strains.

“It’s got a sneaky wrapper on it,” said Bridget Carragher, one of the studies’ authors and professor of integrated structural and computational biology at the Scripps institute. “It mutates rapidly and coats itself with sugars to hide from the immune system. We’ve got to understand what those defenses are so they can be overcome.”

The virus’ malleability also makes it fragile, said John Moore, another study author and professor of microbiology and immunology at Weill Cornell Medical College.

“It has to be somewhat unstable, because it’s a machine that has to move and undergo conformational changes to allow the virus to fuse with the (host) cell,” he said.

Those characteristics have confounded attempts to create an AIDS vaccine, because the trimer structure disintegrates when it’s removed from the virus. Vaccines based on certain constituent parts of a trimer haven’t triggered the right antibodies.

The Scripps and Weill Cornell researchers believe they have overcome that barrier by chemically stabilizing the trimer’s structure — and thereby retaining its key features.

Using X-ray crystallography, one team of researchers analyzed the structure in crystalline form. The other group used cryo-electron microscopy to view the trimer at the atomic level. While neither method had fully succeeded in the past, this time both yielded nearly simultaneous results with the stabilized protein.

“It’s been a project that has been incredibly difficult to start with, so it was important to tackle it from many different approaches,” said Jean-Philippe Julien, a lead author on the project and a senior research associate at the Scripps institute. “Now that we have both techniques yielding that structure, we can compare it directly.”

Moreover, he said, the two techniques discovered different weaknesses in the trimer structure — important because an effective vaccine will have to trigger a multipronged assault on the swiftly shifting virus.

“(HIV) has a high capacity to evolve and evade the immune system,” he said. “So that’s probably why we’ll need immune responses that target multiple sites, so it cannot evolve away from multiple responses.”

Scientists are testing whether the engineered trimer prompts an immune response in animals, and they expect to conduct clinical trials for people, Moore said.

The research methods that he and his colleagues at Scripps and Weill Cornell developed also can be deployed to study other viral diseases such as influenza, hepatitis C and the respiratory syncytial virus, which causes lung infections in young children, said Ian Wilson, a senior author of the trimer research and the Hansen Professor of Structural Biology at the Scripps institute.

“These are extremely useful techniques for investigating pathogens,” he said.